Diabetes is defined as a state in which carbohydrate and lipid metabolism are improperly regulated by the hormone insulin (For review, see, e.g., Saltiel, Cell 104:517-529(2000)). Two major forms of diabetes have been identified, type I and II. Type I diabetes represents the minor form of the disease, affecting 5-10% of diabetic patients. It is thought to result from the autoimmune destruction of the insulin-producing beta cells of the pancreatic Islet of Langerhans. Exogenous administration of insulin typically alleviates the pathophysiology. Type II diabetes is the most common form of the disease and is possibly caused by a combination of defects in the mechanisms of insulin secretion and action. Both forms, type I and type II, have similar complications, but distinct pathophysiology.
Glucose is necessary to ensure proper function and survival of all organs. While hypoglycemia produces cell death, chronic hyperglycemia can also result in organ damage. Following a meal, the level of glucose in the blood is elevated. The balance between the utilization and production of glucose is maintained at equilibrium by two opposing hormones, insulin and glucagon. In response to elevated plasma levels of glucose, pancreatic beta cells secrete insulin. Insulin, in turn, acts on muscle, liver and adipose tissues to stimulate glucose uptake into those cells. When plasma levels of glucose decrease, the pancreatic alpha cells secrete glucagon, which in turn stimulates glycolysis in the liver and release of glucose into the bloodstream.
The first stage of type II diabetes is characterized by the failure of muscle and/or other organs to respond to normal circulating concentrations of insulin. This is commonly associated with obesity, a sedentary lifestyle, as well as a genetic predisposition. This is followed by an increase in insulin secretion from the pancreatic beta cells, a condition called hyperinsulinemia. Ultimately, the beta cells can no longer compensate, leading to impaired glucose tolerance, chronic hyperglycemia, and tissue damage.
The action of glucagon on glycolysis in the liver is mediated by the glucagon receptor. It has been reported that the hyperglycemic state of diabetes mellitus is not only due to glucose under-utilization as a result of decreased insulin, but also to the overproduction of glucose due to elevated concentrations of glucagon (See, e.g., Unger, Diabetes 25:136-151 (1976); Unger and Orci, Lancet 1:14-16 (1975)). The murine glucagon receptor cDNA, gene and promoter region was cloned, sequenced, and its tissue distribution studied (See, e.g., Burcelin et al., Gene 164(2):305 (1995)). The 1944 base pair MRNA cds has been deposited in GenBank (Accession No.: L38613; GI No.: 603463). The murine glucagon receptor was found to contain 13 exons located in a region of 4.0 kb. Moreover, this gene encodes a 485-amino-acid protein consisting of seven putative transmembrane domains. The murine glucagon receptor was found to be expressed predominantly in the liver, kidney, adrenal gland, lung and stomach. Lower levels of expression are detected in brown and white adipose tissue, cerebellum, duodenum and heart. A 1000-bp region of the glucagon receptor promoter has been sequenced. This region contains consensus sequences for putative DNA-binding proteins involved in tissue specificity (c/EBP; HNFI) or hormonal regulation (steroid receptor). Other consensus sequences are those known to function in controlling basal promoter activity, such as AP1 and AP2.
Upon the binding of the glucagon receptor with glucagon, a signal to the cell is transduced, thereby triggering glycogen hydrolysis and glucose synthesis. It has been reported that cyclic adenosine monophosphate (cAMP) mediates the effects of glucagon. The binding of glucagon to its cellular receptor activates adenylate cyclase to produce cAMP, raising the levels of intracellular cAMP. Elevation of intracellular levels of cAMP is believed to result in glycogenolysis and gluconeogenesis, with the resultant rise in glucose production by the liver (See, e.g., Unson et al., Peptides 10:1171-1177 (1989)). Other cellular pathways have also been suggested for the stimulation of glycogenolysis and gluconeogenesis. It has also been reported that glucagon binds to receptors in the hepatocyte membrane that are coupled via a G-protein to phospholipase C. This protein causes the breakdown of phosphatidylinositol 4,5 biphosphate to produce the second messengers inositol triphospate and 1,2 diacylglycerol upon the interaction of glucagon and its receptor (See, e.g., Wakelam et al., Nature 323:68-71 (1986); Unson et al., Peptides 10:1171-1177 (1989); Pittner and Fain, Biochem. J. 277:371-378 (1991)).
Obesity is a disease that affects at least 39 million Americans: more than one-quarter of all adults and about one in five children. Each year, obesity causes at least 300,000 excess deaths in the U.S. and costs the country more than $100 billion. Over the last 10 years, the proportion of the U.S. population that is obese has increased from 25 percent to 32 percent. Obesity is measured by Body Mass Index, or BMI, which is a mathematical calculation used to determine if a person is obese or overweight. BMI is calculated by dividing a person's body weight in kilograms by their height in meters squared. A BMI of 30 or greater is considered obese, while a BMI of 25-29.9 is considered overweight. However, the criteria for diagnosis can be misleading for people with more muscle mass and less body fat than normal, such as athletes. Over 70 million Americans are considered overweight. Health problems, including but not limited to cardiovascular disease, blood pressure, Type II diabetes, high cholesterol, gout, certain types of cancer, and osteoarthritis, are associated with overweight conditions and obesity.
Diabetes and diabetic conditions, as well as weight related conditions, such as obesity, are clearly associated with health problems, and the increase in prevalence of these conditions is a cause for concern. A clear need exists for further analysis and, in particular, in vivo characterization of genes, such as the glucagon receptor, to determine their role in dysfunctions and diseases, such as diabetes or obesity, which may play a role in preventing, ameliorating, or correcting dysfunctions or diseases.